Dear group,
I am currently analyzing some dose-response data for one of our drugs. A
simple Emax model nicely described the dose-response relationship for the
principal PD variable (a continuous measure). Unfortunately, no PK data
was obtained from the subjects in the PD study. Since the variability in
the PD measure was quite high (CV>80% placebo, CV>100% active treatment)
and variability in the AUC from previous PK studies was also high (55%,
mainly due to variable bioavailability), the question is if reducing the
variability in F (better formulation) would also relevantly improve PD
variability.
I have tried the following:
- Adding an ETA to dose in the Emax model with IIV fixed to 55%CV
(IIV_ED50 reduced from 100% to 75%)
- Use the resulting estimates (including IIV_ED50, IIV_Placebo,
residual variability,[Emax was fixed]) to simulate the response for
different values of IIV_dose
- Calculate the overall variability of the response
(Note, that residual variability was also pretty high (approx 100%CV))
The results suggested that the overall PD variability would only decrease
very little by reducing variability in F. However, I am unsure if my
approach is acceptable and would like to have some input from the group.
Thanks in advance, Andreas.
Andreas Lindauer
Pharmacokineticist
Pharmacokinetics and Metabolism
R&D Center. Ferrer Internacional S.A.
Juan de Sada 32, 08028 Barcelona
Tel +34 93 509 3265
Fax +34 93 411 2764
[email protected]
www.ferrergrupo.com
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PK and PD variability
Dear Andreas,
When you say you add IIV on dose, I'm not sure exactly what you mean but
suggest you need to take a 2 step approach. In order to replicate variability
in dose, you will need to simulate doses with variability, and then in a second
step use these simulated doses to estimate the Emax model (note that merely
putting IIV on dose during estimation will not force dose to vary in the way
you want). You can then repeat this process with different dose variabilities
to see how PD parameters change/whether it is worth trying to optimise
formulation.
BW,
Joe
Quoted reply history
________________________________
From: [email protected] [[email protected]] On Behalf Of
[email protected] [[email protected]]
Sent: 11 March 2011 09:47
To: [email protected]
Subject: [NMusers] PK and PD variability
Dear group,
I am currently analyzing some dose-response data for one of our drugs. A simple
Emax model nicely described the dose-response relationship for the principal PD
variable (a continuous measure). Unfortunately, no PK data was obtained from
the subjects in the PD study. Since the variability in the PD measure was quite
high (CV>80% placebo, CV>100% active treatment) and variability in the AUC from
previous PK studies was also high (55%, mainly due to variable
bioavailability), the question is if reducing the variability in F (better
formulation) would also relevantly improve PD variability.
I have tried the following:
- Adding an ETA to dose in the Emax model with IIV fixed to 55%CV
(IIV_ED50 reduced from 100% to 75%)
- Use the resulting estimates (including IIV_ED50, IIV_Placebo, residual
variability,[Emax was fixed]) to simulate the response for different values of
IIV_dose
- Calculate the overall variability of the response
(Note, that residual variability was also pretty high (approx 100%CV))
The results suggested that the overall PD variability would only decrease very
little by reducing variability in F. However, I am unsure if my approach is
acceptable and would like to have some input from the group.
Thanks in advance, Andreas.
[cid:_1_0824135C08240F740035C369C1257850]
Andreas Lindauer
Pharmacokineticist
Pharmacokinetics and Metabolism
R&D Center. Ferrer Internacional S.A.
Juan de Sada 32, 08028 Barcelona
Tel +34 93 509 3265
Fax +34 93 411 2764
[email protected]
www.ferrergrupo.com
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Dear Andreas,
Perhaps one strategy would be to use the data from the previous PK/PD study and
to first fit the PK data. Then fit your nice Emax model based on the PK model
. You could fit simultaneously the PK/PD from the previous study. From this
point you have several path you can take to evaluate your PD study. You can do
a Bayesian analysis using the model from the PK/PD study to get individual
estimates. You can pool the data from the 2 studies and get population and
individual estimates or just use the model from the PK/PD study and fit it with
the data of the PD study.
Best regards,
Jean
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of [email protected]
Sent: Friday, March 11, 2011 4:47 AM
To: [email protected]
Subject: [NMusers] PK and PD variability
Dear group,
I am currently analyzing some dose-response data for one of our drugs. A simple
Emax model nicely described the dose-response relationship for the principal PD
variable (a continuous measure). Unfortunately, no PK data was obtained from
the subjects in the PD study. Since the variability in the PD measure was quite
high (CV>80% placebo, CV>100% active treatment) and variability in the AUC from
previous PK studies was also high (55%, mainly due to variable
bioavailability), the question is if reducing the variability in F (better
formulation) would also relevantly improve PD variability.
I have tried the following:
- Adding an ETA to dose in the Emax model with IIV fixed to 55%CV
(IIV_ED50 reduced from 100% to 75%)
- Use the resulting estimates (including IIV_ED50, IIV_Placebo, residual
variability,[Emax was fixed]) to simulate the response for different values of
IIV_dose
- Calculate the overall variability of the response
(Note, that residual variability was also pretty high (approx 100%CV))
The results suggested that the overall PD variability would only decrease very
little by reducing variability in F. However, I am unsure if my approach is
acceptable and would like to have some input from the group.
Thanks in advance, Andreas.
[cid:[email protected]]
Andreas Lindauer
Pharmacokineticist
Pharmacokinetics and Metabolism
R&D Center. Ferrer Internacional S.A.
Juan de Sada 32, 08028 Barcelona
Tel +34 93 509 3265
Fax +34 93 411 2764
[email protected]
www.ferrergrupo.com
[cid:[email protected]]
¿Necesita imprimir este mensaje? Protejamos el medio ambiente.
Li cal imprimir aquest missatge? Protegim el medi ambient.
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Este mensaje, y en su caso, cualquier fichero anexo al mismo, puede contener
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prohibida su divulgación, copia o distribución a terceros sin la autorización
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This message and its annexed files may contain confidential information which
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Dear Joseph,
I promised to give some feedback on the suggestions you made.
Estimating IIV on F indeed results in a rather high shrinkage for this
parameter (about 65%). However, I don’t think that this might be an issue
in my situation since I will not use EBEs of F for any purpose. The idea
was only to separate the variability in ED50 into PD and PK related
variation. Actually, I think this approach is somewhat similar to the K-PD
modelling explained by Jacqmin et al. 2008. I also applied a
simulation-reestimation procedure, that is, simulating the model including
IIV on F and reestimating with the original model without F. Only IIV on
ED50 was affected, as expected.
Joseph, the approach you described also worked well and led to the same
conclusion: the interindividual variability in the response is dominated
by the variability of the PD and to a much lesser extent by PK.
Thank you once again for your suggestions.
PS: I would still be interested if anyone had a similar problem and how it
was solved.
Andreas Lindauer
Pharmacokineticist
Pharmacokinetics and Metabolism
R&D Center. Ferrer Internacional S.A.
Juan de Sada 32, 08028 Barcelona
Tel +34 93 509 3265
Fax +34 93 411 2764
[email protected]
www.ferrergrupo.com
¿Necesita imprimir este mensaje? Protejamos el medio ambiente.
Li cal imprimir aquest missatge? Protegim el medi ambient.
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destinatario, quedando prohibida su divulgación, copia o distribución a
terceros sin la autorización expresa del remitente. Si Vd. ha recibido
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This message and its annexed files may contain confidential information
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"Standing Joseph (GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS TRUST)"
<[email protected]>
11/03/2011 16:46
Para
"[email protected]" <[email protected]>
cc
Asunto
RE: [NMusers] PK and PD variability
Andreas,
I think the method you describe will not give the required variability -
what will happen is that during $ESTIMATION NONMEM will assign individual
F values that best fit the model, they won't necessarily vary with a CV of
55%. (You can prove this to yourself by outputting F in a table and
plotting it/checking if the ETA values really do have a CV of 55%, or
looking at shrinkage on that parameter). So I suggest this:
STEP 1: Simulate new doses for your dataset with variability
$INPUT ...DOSE...
.....
NDOSE = DOSE*EXP(ETA(XXX))
....
$OMEGA XXX ; put variance here
$SIM ; Just do 1 sample but you might want to try a few runs with
different seed numbers if your dataset is small
...
$TABLE ....NDOSE
NDOSE is now your new dose, that have a mean value of the actual dose
given but will be simulated to vary according to $OMEGA
STEP 2: Put variable doses into dataset and estimate Emax model
i.e. put NDOSE instead of DOSE in your dataset
Repeat steps 1 and 2, but change the OMEGA in step 1 to see the effect of
decreasing variability in F on parameter estimates in step 2.
BW,
Joe
Quoted reply history
________________________________________
From: [email protected] [[email protected]] On
Behalf Of [email protected]
[[email protected]]
Sent: 11 March 2011 14:10
To: [email protected]
Subject: RE: [NMusers] PK and PD variability
Joseph,
with adding IIV on dose I meant multiplying DOSE in the Emax model with a
bioavailability parameter F with its theta fixed to 1 and omega fixed to
55% CV:
E.g.:
IPRED = BL + EMAX * F*DOSE/(ED50+F*DOSE)
where F = theta(F)*exp(eta(F))
Sorry for not being clear. Regards, Andreas.
[cid:_1_0853B75C0853B374004DDB45C1257850]
Andreas Lindauer
Pharmacokineticist
Pharmacokinetics and Metabolism
R&D Center. Ferrer Internacional S.A.
Juan de Sada 32, 08028 Barcelona
Tel +34 93 509 3265
Fax +34 93 411 2764
[email protected]
www.ferrergrupo.com
[cid:_1_0853F8700853F4B4004DDB45C1257850] ¿Necesita imprimir este
mensaje? Protejamos el medio ambiente. Li cal imprimir aquest missatge?
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********************************************************************************************************************
This message may contain confidential information. If you are not the
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Thank you for your co-operation.
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